Oleaginous systems



3,1163%?) GLEAGINOUS SYSTEMS .lohn Kariss, Clifton, and Harold Leon Newmark, Maplewood, Ni, assignors to Hoffmann-La Roche Inc, Nutley, N.J., a corporation of New Jersey No Drawing. Filed Mar. 14, 1962, Ser. No. 179,894 8 Claims. (Cl. 16765) The present invention relates to parenterally acceptable non-aqueous diluents for physiologically active compounds of the benzodiazepine type and to parenteral solutions containing these compounds.

Benzodiazepines having the following formula wherein R is halogen, trifluoromethyl, or nitro, R is hydrogen or lower alkyl, e.g. methyl; and R is hydrogen, trifiuoromethyl, or halogen; and the corresponding 4-oxide and 4,5-dihydro derivatives are useful as muscle relaxants, anticonvulsants, and tranquilizers. The term halogen used above includes fluorine, chlorine, bromine, and iodine.

For some applications non-aqueous parenteral solutions of the above compounds are desired. However, the above compounds have a low solubility in the usual nonaqueous parenteral diluents, and accordingly, parenteral solutions of these compounds generally cannot be formed to contain a sufficient quantity of the benzodiazepine to be useful, e.g. in the veterinary field, where large animals require large total drug dosages.

The present invention relates to novel parenterally acceptable non-aqueous diluents for the above benzodia- Zepines which will dissolve a suflicient quantity of benzodiazepine to form solutions thereof which are useful, e.g. in the veterinary field.

Examples of the benzodiazepines which are solubilized by the parenterally acceptable diluents of the invention include:

the invention contain (1) from about 1% to about 30%, preferably about to about dimethyl acetamide,

} United States Patent 0 "ice (2) from about 1% to about 10%, preferably about 2% benzyl alcohol, and at least 30% of a parenterally ac ceptable non-aqueous vehicle, i.e. those described under the heading Other Vehicles, page 818, U.S. Pharmacopeia XVI; examples of which are the fixed oils, and synthetic monoor di-glycerides of fatty acids. Specific examples include isopropyl myristate, sesame oil, etc. The quantity of vehicle will vary according to the quantities of other ingredients employed, but in no case will be less than about 30%. An optional but preferred component is from about 1% to about 30%, preferably about 10% ethanol. Small quantities of other ingredients such as preservatives, antioxidants, e.g. free tooopherols, Ibutylated hydroxyanisole, butylated hydroxy-toluene, propyl gallate, etc., can also optionally be employed.

It has surprisingly been found that the instant nonaqueous diluent compositions (which are free flowing liquids at 25 C.) containing a benzodiazepine of the invention, exhibit rapid onset of activity upon injection, in contradistinction to the slow onset of activity encountered with many drug containing non-aqueous parenteral diluent compositions of the prior art.

However, for some applications, slow onset of activity may actually be desirable. For example, a semi-solid benzodiazepine composition having a slow drug release rate in the body is desired by use in injection gums and other devices of this type. The composition is packed into injection cartridges as a warm liquid which then sets into a semi-solid upon cooling. When extruded through the orifice of a needle into body tissues, the composition forms a repository which releases the drug slowly into the body. Hence, the invention in another of its aspects relates to parenteral diluent compositions which are semisolid at room temperature and which contain a minor amount of a thickening agent in addition to the ingredients listed above for the diluent compositions of the invention. The thickening agents that can be employed are from about 5% to about 20%, preferably about 8% to about 10% beeswax; from about 1% to about 4%, preferably about 2% to about 3% aluminum monostearate; from about 5% to about 20%, preferably about 7% to about 10% of a polyethylene glycol polymer (or mixture of polymers) having a molecular Weight of at least 4000; from about 5% to about 50%, preferably about 30% to about 40% hydrogenated fixed oil, e.g. hydrogenated coconut oil; and from about 1% to about 4%, preferably about 2% ethyl cellulose (e.g. Ethocel).

The percentages given above and elsewhere in the application are percentages by weight and are based on the total weight of the diluent composition unless otherwise noted. It is also to be noted that the term. dimethyl acetamide as used herein means N,N-dimethyl acetamide.

The invention in another of its aspects relates to a solution of a benzodiazepine in a diluent of the invention. The weight of a benzodiazepine which is employed per cc. of diluent will, in general, range from about 5 to about 15 0, preferably about 25 to about 50 mg. In some cases the upper limit of the above range will be determined by the maximum solubility of the compound in [the diluent, which may be less than the upper limit given above.

The liquid solutions of benzodiazepines of the invention are useful for parenteral injection when rapid action is required or oral administration is not feasible, e.g. in the veterinary field. Routes of parenteral injection include intramuscularly, subcutaneously, and intrapenitoneally. These liquid solutions are particularly suitable for veterinary parenteral use, since the benzodiazepine compounds are highly soluble therein so that large doses of these compounds can be administered without necessitating the use of a large volume of solution. The semisolid compositions of the invention are similarly useful 3, where slow release of drug is desired. The quantity of a parenteral benzodiazepine composition of the invention which is administered to an animal will depend on the particular animal, the weight of the animal, the purpose for which it is administered, the diagnosis, etc.

The invention will be better understood from the following examples which are given for illustration purposes only and are not meant to limit the invention.

EXAMPLE 1 A diluent suitable for parenteral use is prepared by mixing the following ingredients together:

Each ml. Dimethyl acetamide rnl 0.100 Ethyl alcohol ml 0.100 Benzyl alcohol m l 0.015

Sesame oil, q.s. to 1 ml.

50 mg. of 7-chloro-5-phenyl-1-methyl-3H-1,4-benzodiazepin-2(1H)-'one is dissolved in 1 ml. of the above diluent. The resulting solution is suitable for parenteral injection, e.g. intramuscularly.

Each of the following compounds is dissolved in 1 ml. of the above diluent, the quantity being dissolved being 50 mg. per ml. or, where the solubility is less than 50 mg. per ml., a saturated solution is formed:

7-chloro-2-oxo-5-phenyl-1,2,4,5-tetrahydro-3H-1,4-benzodiazepine, 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazeipin-2(1H)- one 4-oxide, 7-ohloro-5-( 2-chlorophenyl) -3H-1,4-benzodiazepin- 2( 1H) -one, 7-nitro-5-.(2-chlorophenyl) -3H-1,4-benzodiazepin-2( 1H) one, 7-chloro-2-oxo-5-phenyl-1,Z-dihydro-3H-1,4-benzodiazepine, 7-nitro-5-phenyl-3H-1,4-benzodiazepin-2( 1H) -one, 'l-IlillIO-S-(a,oc,a-lrlfi11OFO-OtOlyl) -3H-benzodiazepin- 2'( 1H) -one, 7-nitrol-methyl-S- (Z-fluorophenyl) -3H1,4-benzodiazepin-2( 1H) -one, 5-phenyl-7-trifluor0methyl-3H-1,4-benzodiazepin-2( 1H) one, 7-chloro-2-oxo-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepine 4-oxide, etc.

EXAMPLE 2 A diluent suitable for parenteral use is prepared by mixing the following ingredients together:

Each ml. Dimethyl acetamide ml 0.100 Ethyl alcohol ml 0.100 Benzyl alcohol ml 0.015

Isopropyl myristate, q.s. to 1 ml.

50 mg. of 7-chloro-5-phenyl-1-methyl-3H-1,4-benzodiazepin-2(1H)-one is dissolved in 1 ml. of the above diluent. The resulting solution is suitable for parenteral injection. Each of the other compounds of Example 1 is dissolved in 1 ml. of the above diluent, the quantity being dissolved being 50 mg. per ml. or, where the solubility is less than 50 mg. per ml., a saturated solution is formed.

EXAMPLE 3 A diluent suitable for parenteral use is prepared by mixing the following ingredients together:

Each ml. Dimethyl acetamide ml 0.300 Ethyl alcohol rnl 0.100 Benzyl alcohol ml 0.100

Sesame oi-l, q.s. to 1 ml.

100* mg. of 7-chloro-5-phenyl-1methyl-3H-1,4-benzodiazepin-2(1H)-one is dissolved in 1 ml. of the above diluent. The resulting solution is suitable for parenteral injection.

Each of the other compounds of Example I is dissolved Cir i in 1 ml. of the above diluent, the quantity being dissolved being 50 mg. per ml. or, where the solubility is less than 50 mg. per ml., a saturated solution is formed.

EXAMPLE 4 The diluent and compositions of Example 3 were made up as disclosed in Example 3, except that isopropyl myristate, q.s. to 1 ml. is employed in place of sesame oil.

EXAMPLE 5 A semi-solid diluent composition suitable for parenteral use is prepared by mixing the following ingredients together:

Each ml. Dimethyl acetamide inl 0.300 Benzyl alcohol ml 0.100 Beeswax mg 0.080

Sesame oil, q.s. to 1 ml.

The mixture is heated together to about 85 C. to effect solution.

To the above hot solution, 134 mg. of 7-chloro-5-ohenyl 1 methyl-3H-l,4-benzodiazepin-2(1H)-one is added per ml. and stirred until the compound is in solution. The hot solution is then filled into injection cartridges and allowed to cool.

Each of the other compounds of Example 1 is dissolved in 1 ml. of the above diluent, the quantity being dissolved being chosen from the range of 5 to mg. per ml. as desired.

Many of the compounds of Formula I and their 4- oxide and 4,5-dihydro derivatives are known. However, some of the compounds are not known, and accordingly, methods for their preparation are given below for purposes of completeness. However, it should be understood that neither the compounds of Formula I per se nor methods for their preparation are within the scope of the invention.

7-Chlor0-5-(Z-Chlorophenyl) -3H-1,4-Benzodiazepin- 2(1H)-One o-Chlorobenzoylchloride (600 g.) was heated to 110 in a 5 l. three-necked flask equipped with thermometer, mechanical stirrer, and reflux condenser. To this pchloroanilin g.) was added under stirring. The mixture was then heated to and zinc chloride (230 g.) was added. The temperature now was gradually raised to 220-230" and kept there until the HCl evolution had ceased (1-2 hours). After cooling to 120, Water was cautiously added and the mixture heated to reflux. The hot water layer was decanted and this procedure repeated 2 or 3 times.

The water insoluble brown mass was finally suspended in a mixture of 350 ml. Water, 50 0 ml. acetic acid and 650 ml. cone. sulfuric acid and heated to reflux for 17 hours. After cooling, the homogeneous dark solution was poured into ice water, the mixture extracted with ether, the ether extract was neutralized with 2 N NaOH. Cone. of the ether solution and addition of a small amount of petroleum ether yielded 2- amino-2,5-dichlorobenzophenone in yellow crystals, which after recrystallization from ether petroleum ether yielded the pure compound, M.P. 8889.-

2-amino-2',S-dichlorobenzophenone (112 g.) was dissolved in a solution containing glycine ethyl ester hydro chloride (180 g.) in pyridine (500 ml.) and piperidine (5 ml.). After refluxing for 18 hours, the solvents were evaporated, the residue taken up in ether and the ether extract washed with water. The ether phase was repeatedly extracted with 2 N HCl thus separating the salt of the reaction product from the unreacted ketone which remains in the ether. The acidic aqueous solution was neutralized and extracted with ether to yield 7-chloro-5- (2 chlorophenyl) 3H 1,4 benzodiazepin 2(1H) one. After recrystallization from methanol the product forms crystals melting at 199-201".

A mixture of 16.8 g. of 2arninobenzophenone, 11.9 g. of glycine ethyl ester hydrochloride and 200 cc. of pyridine was heated to reflux. After one hour, 20 cc. of pyridine was distilled off. The solution was refluxed for 15 hours, then 11.9 g. of glycine ethyl ester hydrochloride was added and the refluxing was continued for an addi tional 4 hours. The reaction mixture was concentrated in vacuo, then diluted with ether and water. The reaction product, S-phenyl-SH-l,4-benzodiazepin-2(1H)-one, crystallized out, was filtered oil, and then recrystallized from acetone in the form of colorless rhombic prisms, ALP. 182183.

The above mentioned 5-phenyl-3l-1-l,4-benzodiazepin- 2(1H)-one is not a part of this invention but its preparation is set forth above in order that this disclosure may be complete.

12 g. (0.05 mol.) of 5-phenyl-3l-d, i-benzodiazepin- 2(1H)-one was dissolved in 16 cc. of concentrated sulfuric acid by stirring at room temperature for /2 hour. To the solution there was then added dropwise a cooled mixture of 3.5 cc. of concentrated sulfuric acid and 3.5 cc. of fuming nitri acid (90%, sp. gr.=1.50). The temperature of the reaction mixture slowly rose to 40. The mixture was then stirred at 30 for 2 hours and allowed to stand at room temperature overnight. The reaction mixture was poured on 1 kg. of crushed ice with stirring and stirred for 2 hours. The yellow precipitate was then filtered off, washed with about 1.5 liters of ice water and dried o ernight.

The crude product was ground and suspended in 200 cc. of water containing 50 cc. of 20% sodium acetate solution and a few drops of antifoam agent. After stirring for about A2 hour, the mixture was no longer acid to congo red paper. The precipitate was then filtered off, washed with water and sucked dry. The product, 7,9- dinitro 5 phenyl 3H 1,4 benzodiazepin 2(1H) one, was crystallized twice from 40% ethanol, and obtained as yellow needles melting at 240.

48 g. (0.2 mol.) or" 5-phenyl-3H-1,4-benzodiazepin- 2(1H)-one was dissolved in 250 cc. of concentrated sulfuric acid by stirring at 15 for /2 hour. The solution was then cooled to and a mixture of 9.1 cc. of fuming nitric acid (90%, sp. gr.=1.50) and 11.8 cc. of concentrated sulfuric acid was added dropwise with stirring, keeping the temperature of the reaction mixture between and 0". liter completion of the addition of the nitric acid-sulfuric acid mixture, stirring was continued for 1 hour and the reaction mixture was stored in the refrigerator overnight.

The mixture was then added dropwise to 2 kg. of crushed ice with stirring and cooling, keeping the temperature at 0. After 1 hour of stirring in the cold, 640 cc. of concentrated ammonium hydroxide was added dropwise at 0 to pH 8. Stirring was continued for /2 hour and the crude product was filtered off, washed with a small amount of ice water and sucked dry overnight. The crude product was suspended in a mixture of 100 cc. of methylene chloride and 1700 cc. of alcohol. 50 g. of decolorizing charcoal was added and the mixture was refluxed with stirring for 2 hours. After standing overnight at room temperature 15 g. of diatomaceous earth filter aid was added and the refluxing was resumed for 1%. hours. The mixture was filtered while hot. The clear, light yellow filtrate was concentrated in vacuo on the steam bath with stirring to about 600 cc. The concentrate was stirred and cooled in ice for about 2 hours; the precipitated crystalline product was filtered off, washed with some petroleum ether and sucked dry. The product, 7-nitro-5-phenyl-3H-1,4-benzodiazepin 2(1H) one, was recrystallized from a mixture of 1000 cc. of alcohol and 50 cc. of methylene chloride to obtain white prisms melting at 224- 225.

6 7 -N itro-S Z-Chl oroplzenyl -3H ,4-Benzodiazepin- 2 (l H) -One A stirred solution of 75 g. of 2-amino-2'-nitrobenzo phenone in 700 ml. of hot concentrated hydrochloric acid was cooled to 0 and a solution of 21.5 g. of sodium nitrite in 50 ml. of water was added in the course of 3 hours. The temperature of the suspension was kept at 27 during the addition. The resulting clear solution was poured into a stirred solution of 37 g. of cuprous chloride in 350 ml. of hydrochloric acid 1:1. The solid which had formed after a few minutes was filtered off, washed with water and recrystallized from ethanol. Crystals of 2-chloro-2'-nitrobenzophenone melting at 7679 were obtained.

A solution of 20 g. of 2-chloro-2-nitrobenzophenone in 450 ml. of ethanol was hydrogenated at normal pressure and room temperature with Raney nickel. After uptake of ca. 6 liters of hydrogen the catalyst was filtered off, and the alcohol then removed in vacuo. The residue was distilled in a bulb tube at 0.4 mm. and a bath temperature of 150-165 giving a yellow oil. The oil was dissolved in alcohol, and on addition of water, needles of 2-amino2'-chlorobenzophenone melting at 5860 were obtained.

To a solution of 42 g. of 2-amino-2'-chlorobenzophenone in 500 ml. of benzene, 19 ml. of bromoacetyl bromide was added dropwise. After refluxing for 2 hours, the solution was cooled, washed with 2 N sodium hydroxide and evaporated. The residue was recrystallized from methanol giving crystals of 2-bromo-2-(2-chlorobenzoyl) acetanilide melting at 119-121 To a solution of 14.5 g. of 2-bromo-2-(2-chlorobenzoyl)acetanilide in ml. of tetrahydrofuran, an excess of liquid ammonia (ca. 150 ml.) was added. The ammonia was kept refluxing with a Dry-Ice condenser for 3 hours after which time the ammonia was allowed to evaporate and the solution was poured into water. Crystale of 2 amino 2-(2-chlorobenzoyl)acetanilide were collected, which after recrystallization from ethanol mel ed at 162-164.

A solution of 3 g. of 2-amino-2'-(2-chlorobenzoyl)- acetanilide in 50 ml. of pyridine was refluxed for 24 hours after which time the pyridine was removed in vacuo. The residue was recrystallized from methanol and a mixture of dichloromethane and ether giving crystals of 5-(2-chlorophenyl) 3H 1,4 benzodiazepin-2(1H)-one melting at 212-213.

The 5 (Z-chlorophenyl)-3I-I-1,4-benzodiazepin-2(1H)- one mentioned above is not a part of this invention but intermediates therefor and its preparation are set forth above in order that this disclosure may be complete.

To a solution of 13.5 g. of 5-(2-chlorophenyl)-3H-1,4- benzodiazepin-2(1H)-one in 60 ml. of concentrated sulfuric acid, a solution of 5.5 g. of potassium nitrate in 20 ml. concentrated sulfuric acid was added dropwise. The solution then was heated in a bath at 4550 for 2% hours, cooled and poured on ice. After neutralizing with ammonia, the formed precipitate was filtered off and boiled with ethanol. A small amount of white insoluble material was then filtered off. The alcoholic solution on concentration yielded crystals of 7-nitro-5-(2-chlorophenyl)-3H-1,4-benzodiazepin-2(1H)-one which, after recrystallization from dichloromethane, melted at 23 8- 240.

A solution of o-trifluoromethyl phenyl magnesium bromide was prepared in the usual manner from 50.0 g. of o-bromobenzotrifluoride, 5.55 g. of magnesium and ml. of anhydrous ether. The Grignard reagent can also be prepared by reacting 39.7 g. of o-chlorobenzotrifluoride with 5.55 g. of magnesium in tetrahydrofurane. This solution was added with stirring at 20 C. over a period of 3 hours to a solution of 33.0 g. of 2-methyl-4H-3,lbenzoxazin-4-one in 300 ml. of methylene chloride. The resulting dark but clear solution was left at room temperature for 16 hours and was then poured over a mixture of 50 g. of ammonium chloride and 600 g. of crushed ice. Extraction with ether gave a crude reaction product which was directly hydrolyzed by refluxing for one hour in a mixture of 240 ml. of ethanol and 240 ml. of 3 N sodium hydroxide. After standing overnight, the reaction mixture was extracted with ether. The ether layer was washed with water and concentrated in vacuo yielding an oil. This was purified in two portions by chromatography on the 20-fold amount of neutral alumina (activity grade III; e.g. containing 6% of water). Elution with petroleum ether (6070) and a mixture of petroleum ether (6070) and ether (9:1) followed by crystallization from a mixture of ether and hexane yielded 2-amino- 2'-trifiuoromethylbenzophenone, melting at 9496 (yellow prisms).

, To a solution of 5.0 g. of 2-amino-2trifluoromethylbenzophenone in 25 ml. of anhydrous ether, cooled to C., 1.7 ml. of bromoacetylbromide was added with stirring; at precipitation occurred and the yellow color of the solution gradually faded. The suspension containing 2 bromoacetamido 2 trifluoromethylbenzophenone (not isolated) was stirred for half an hour at 0 C. and for two hours at room temperature. After that, 25 ml. of liquid ammonia was condensed into the flask, by introducing ammonia gas and using an efiicient Dry Ice-acetone condenser. The resulting mixture was stirred and refluxed (B.P. of liquid ammonia) for 3 hours. After taking off the condenser, the ammonia was allowed to evaporate overnight. The reaction mixture was extracted with ether (the ether layers being washed 3 times with water) and yielded crude 2-amino-2'-(2-trifiuoromethylbenzoyl)acetanilide. Recrystallization from a, mixture of 15 ml. of benzene and 15 ml. of hexane gave the pure product, melting at 141-142" C. (colorless, rhombic plates).

3.0 g. of 2-arnino-2-(Z-trifluoromethylbenzoyl)acetanilide was heated in an open tube for 15 minutes to 200- 205 C., using an oil bath. Water was given off. On cooling, a brown glass was obtained which, on crystallization from a mixture of methanol and ether, gave crude 5 (2 trifiuoromethylphenyl) 3H 1,4 benZodiazepi-n- 2(1H)-one. The mother liquor was evaporated to dryness, dissolved in benzene and chromatographed on 60 g. of neutral alumina (activity grade Ill, e.g. containing 6% of water). Elution with benzene (300 ml.) gave a product which could be crystallized to give some starting material. Then, with a benzene-ether-(l:1)-mixture (400 ml), a crude product could be eluted. This, on crystallization from ether-hexane, gave the pure 5-(2-trifluoromethylphenyl)-3H-1,4-benZodiazepin-2(1l-l)-one, melting at 187188 (almost colorless prisms).

7.3 g. of 5-(Z-trifiuoromethylphenyl)-3H-1,4-benzodiazepin-2(1H)-one were dissolved at 0 in 58.4 ml. of concentrated sulfuric acid. To this, over a period of about minutes, 3.22 g. of potassium nitrate were added with stirring. After keeping the reaction mixture for 30 minutes at 0, it was allowed to stand for one hour at Finally, it was heated to 50 for 3 hours. After standing overnight at 25, the yellow solution was poured over 250 g. of ice and the precipitate obtained, filtered and thoroughly washed with diluted ammonium hydroxide solution, diluted acetic acid and water. Crystallization from acetone-benzene of the thus-obtained crude product afforded the 7-nitro-5-(2'-trifiuoromethylphenyl)- 3I-I-1,4-benzodiazepin-2(1H)-one. From the mother liquor and the filtrate, a second crop could be obtained. An analytical sample was prepared by recrystallization from acetone-methanol. Slightly yellow prisms (hexagonal), melting at 233234, were obtained.

8 7-Nz'Ir0-5-(Z-Fluorophenyl) -3H-l ,4-Benz0diazepin- 2(1H) -One A mixture of 176 g. of ortho-fiuoro benzoyl chloride and 64 g. of para-chloroaniline was stirred and heated to 180, at which temperature 87 g. of zinc chloride was introduced, the temperature raised to 200205 and maintained there for forty minutes. The golden colored melt was quenched by the careful addition of 500 ml. of 3 N hydrochloric acid and the resulting mixture refluxed for five minutes. The acid solution was decanted and the process repeated three times to remove all orthofiuorobenzoic acid. The grey granular residue was dissolved in 300 ml. of percent (vol./vol.) sulfuric acid and refluxed for forty minutes to complete hydrolysis. The hot solution was poured over 1 kg. of ice and diluted to two liters with water. The organic material was extracted with four 300 ml. portions of methylene chloride, and the combined extracts subsequently washed with two 500 ml. portions of 3 N hydrochloric acid to remove traces of par-a-ohloroaniline, three 500 ml. portions of 5 N sodium hydroxide solution to remove ortho-lluorobeuzoic acid, and finally two 200 ml. portions of saturated brine solution. The combined methylene chloride extracts were dried over anhydrous sodium sulfate and the solvent removed to give the crude 2-amino-5-chloro-2'-fiuorobenzophenone which upon recrystallization from methanol formed yellow needles melting at 94-95".

50.0 g. of Z-amino-S-chloro-2'-fiuorobenzophenone in 300 cc. of tetrahydrofuran was hydrogenated at atmospheric pressure in the presence of 10 g. of charcoal (Norite), 30.0 g. of potassium acetate and 2.5 cc. of a 20 percent palladous chloride solution (20 percent by weight of palladium). After an initiation period varying from ten minutes to an hour, hydrogen uptake was rapid and stopped completely after the absorption of the theoretical amount. Filtration of the catalyst over a Hyfio pad and removal of the solvent left a yellow crystalline residue. The crude mixture of ketone and potassium acetate was partitioned between methylene chloride (300 cc.) and Water (1 1.). The layers were separated and the water layer washed with methylene chloride (3 x 50 (10.). The organic layers were combined, washed with 3 N sodium hydroxide solution (2 x 50 cc.), water (3 x cc.), dried over anhydrous sodium sulfate and filtered. The solvent was removed and the product recrystallized from ethanol to give 2- amino-2-fiuorobenzophenone as yellow prisms melting at 126128.

A solution of 21.5 g. of 2-amino-2-fiuorobenzophenone in 500 cc. of ether was treated with 20 cc. of a 20 percent (v./v.) solution of bromoacetyl bromide in ether. The mixture was shaken and allowed to stand for five minutes and then washed with water (20 cc). The process was repeated five times. The final solution was washed thoroughly with water (5 x 500 cc.) and concentrated to 100 cc. The crystals were filtered and recrystallized from methanol to give 2-bromacetamido-2-fiuorobenzophenone as white needles melting at 117118.5.

-A solution of 23.7 g. of 2-bromoacetamido-2-fiuorobenzophenone in tetrahydrofuran (100 cc.) was added to liquid ammonia (approximately 500 cc.), and allowed to evaporate overnight. The residue was treated with water (1 l.) and the crystals filtered off and refluxed in toluene (100 cc.) for thirty minutes. The mixture was treated with decolorizing carbon (Norite) and filtered over Hyfio. The solution was concentrated to a small volume (25 cc.) cooled, diluted with 20 cc. of ether and allowed to stand. The product was recrystallized from acetone/hexane to give 5-(2-fiuorop henyl)3H-1,4-benzodiazepin-2(1I-l)-one as white needles melting at -181".

23.8 g. of 5-(2-fiuorophenyl) 3H 1,4 benzodiazepin- 2(1I-I)-one was :dissolved in 50 cc. of concentrated sulfuric acid at 0. To the resulting mixture there was then added dropwise with stirring a solution of 7.1 g. of potassium nitrite in 20 cc. of concentrated sulfuric acid.

The mixture was stirred for 2 /2 hours at and .then diluted with 300 g. of ice. The resulting solution was made alkaline with concentrated ammonium hydroxide solution, keeping the temperature at 0. The formed suspension was extracted thoroughly with methylene chloride (6x 100 ed). The organic layers were combined, washed with saturated brine solution, dried over anhydrous sodium sulfate, and filtered. Removal of the solvent yielded a brown gum which was taken up in a small amount of methylene chloride and filtered through a pad of grade I alumina. The alumina was eluted with methylene chloride, the solvent removed, and the residue crystallized from acetone/hexane to yield 7-nitro-5-(2- fluorophenyl) -3H-1,4-benzodiazepin-2 1H) -one as white needles melting at 210-211.

A solution of 11 g. of this product in a mixture of 150 ml. of ethanol and 100 ml. of 3 N hydrochloric acid was heated on a steam bath for 12 hours. The mixture was diluted with 100 ml. of water and allowed to cool to room temperature. The crystalline product was filtered, washed with water, dissolved 200 ml. of methylene chloride, dried over anhydrous sodium sulfate, filtered, concentrated to a small volume, and diluted with other, whereupon the product crystallized yielding Z-amino-S-nitro-Z-fiuorobenzophenone as yellow needles melting at 154-158? 20.2 g. of the above mentioned 7-nitro-5-(2-fluorophenyl)-3H-1,4-benzodiaZepin-2(1H)-one was dissolved in 60 cc. of N,N-dimethyl formamide to which was then added 3.49 g. of a 50% suspension of sodium hydride in heavy mineral oil. The mixture was allowed to stir for 15 minutes in the cold, 11.2 g. of methyl iodide was added and the solution was stirred for a further 20 minutes. Solvent was removed under reduced pressure to give an oil which was partitioned between water and methylene chloride (1 l./300 cc.), the water layer was extracted with methylene chloride (x200 cc.), the organic layers combined washed with water (2x 100 cc.), 3 N hydrochloric acid (1 X 50 cc.), water (3 X 100 cc.), dried over anhydrous sodium sulfate and filtered. Removal of the solvent gave an oil which was taken up in ether and filtered through a pad of Woelm grade I alumina. The eluent was concentrated and the residue was crystallized from methylene chloride/hexane yielding 1 methyl-7-nitro-5-(2-fiuorophenyl)-3H-1,4-benzodiazepin-2(1H)-one as pale yellow needles melting at 166-167".

80 g. of sodium nitrite were added slowly with stirring to 460 ml. of concentrated surfuric acid. After heating to 70, a clear solution was obtained. This solution was cooled and 200 g. of 2-chloro-5-trifiuoromethylaniline were slowly added at a temperature between and The reaction mixture was stirred for one hour at 20 and then poured onto a mixture of 200 g. of sodium chloride and 1.6 kg. of ice. Excess sodium chloride was filtered off. A solution of 280 g. of zinc chloride in 300 ml. of water was added to the filtrate whereupon a zinc chloride double salt of the corresponding diazonium compound precipitated. After standing overnight at 0, the double double salt was filtered ed and washed with a cold saturated salt solution.

To a solution of 120 g. of sodium cyanide and 72 g. of cuprous cyanide in 300 of water were added with stirring and cooling with ice, 291 g. of the Wet zinc chloride double salt. After the addition of 24 g. of sodium carbonate, the mixture was first stirred for one hour at 20 and then at 70 for an additional /2 hour. The reaction mixture was cooled and extracted with ether to obtain crude 2-chloro-5-tritluoromethylbenzon-itrile. The product was purified by steam distillation and crystallization of the organic part of the distillate from hexane to give the pure compound, M.P. 39-40.

To a solution of phenyl magnesium bromide, prepared from 9.5 g. of magnesium, 58.5 g. of bromobenzene and 500 ml. of anhydrous ether, was added with stirring a solution of 39 g. of 2-chloro-5-trifluoromethylbenzonitrile in 200 ml. of benzene. 400 ml. of solvent were distilled off and the reaction mixture was then refluxed for 16 hours. The Grignard complex was decomposed with 40 g. of ammonium chloride and 200 g. of ice. The mixture was then extracted with benzene. 2-chloro-5-trifluoromethylbenzophenone imine hydrochloride was precipitated from the benzene solution by the addition of 40 ml. of concentrated hydrochloric acid. The product was filtered oif, washed with benzene and dried in vacuo, MP. 248-251, and upon further purification melted at 250- 262.

60 g. of Z-chloro-S-trifiuoromethylbenzophenone imine hydrochloride were refluxed overnight with a mixture of 300 ml. of toluene and 300 ml. of 25% sulfuric acid While stirring. The toluene layer was separated, washed with water, dried, concentrated in vacuo and the residue crystallized from hexane to yield pure 2-chloro-5-trifluoromethylbenzophenone, Ml. 39-40 (corr.).

50' g. of 2-chloro-5-trifiuoromethylbenzophenone and 500 ml. of concentrated aqueous ammonia were reacted in a closed vessel for 10 hours at in the presence of 10 g. of cuprous chloride catalyst. The reaction product was extracted with ether. The ether extract was concentrated in vacuo, the residue dissolved in hexane and purified by chromatography using a 10 fold amount of neutral alumina (Brockmann activity state ll). Elution with a hexane-ether mixture (1:1) and evaporation of the solvent gave 2-amino-5-trifiuoromethylbenzophenone which was recrystallized from hexane to give yellow crystals, MP. 81-82 (corn).

2 g. of 2-amino-S-trifiuoromethylbenzophenone in 50 ml. of pyridine were refluxed for 1 /2 hours with 2.0 g. of glycine ethyl ester hydrochloride. After that, another 1.0 g. of glycine ethyl ester hydrochloride in 2 ml. of pyridine were added. Then 3 m1. of the solvent were distilled off. Refluxing was continued for an additional 2 /2 hours. The reaction mixture was extracted with benzene, the organic layer was Washed with water and dried over sodium sulfate. After evaporation of the solvent, a crude oil was obtained which was dissolved in hexane. After 2 days at 0, the precipitated pure crystalline 7-trifiuoromethyl 5 phenyl-3H-1,4-benzodi azepin-2(1H)-one was filtered off. It melted at 198-199.

By reducing 7 trifluoromethyl-5-phenyl-3H-l,4-benzodiazepin-2(1H)-one with one molar proportion of hydrogen in glacial acetic acid at room temperature and atmospheric pressure in the presence of platinum oxide catalyst, 7 trifluoromethyl-S-phenyl-4,5-dihydro-3H-l,4- benzodiazepin-2 (1H) one is obtained.

By using a-alanine methyl ester hydrochloride instead of the glycine ethyl ester hydrochloride, 7-triiluor0methyl-3-methyl-5-phenyl-3H-l,4-benzodiazepin-2( 1l-l)-one is obtained.

It is to be noted that the term dimethyl ace'tamide as used herein means N,N-dimethyl acetamide.

We claim:

1. A nonaqueous composition suitable for parenteral injection comprising a compound selected from the group consisting of (a) a benzodiazepine having the formula wherein R is selected from the group consisting of halogen, trifluoromethyl, and nitro, R is selected from the group consisting of hydrogen and lower alkyl, and R is selected from the group consisting of hydrogen, trifiuoromethyl, and halogen, (b) 4-oxide derivatives of (a), and (c) 4,5-dihydro derivatives thereof, in a diluent comprising (1) from about 1 percent to about 30 percent by Weight of dimethyl acetami de; (2) from about 1 percent to about 10 percent by weight of benzyl alcohol; and (3) at least 30 percent by Weight of a parenterally acceptable ncnaqueous vehicle; the percents by weight being based on the total weight of the diluent.

2. A composition according to claim 1 which contains a minor amount of a thickening agent.

3. A composition according to claim 1 which contains from about 1% to about 20% ethanol.

4. A composition according to claim 1 which contains from about 10% to about 2.0% dimethyl acetamide and about 2% benzyl alcohol.

5. A composition according to claim 1 wherein the non-aqueous vehicle is isopropyl myristate.

6. A composition according to claim 1 wherein the non-aqueous vehicle is sesame oil.

7. A composition according to claim 1 wherein the quantity of benzodiazepine is in the range of from about 5 mg. to about 150 mg. per ml. of diluent.

8. A composition according to claim 7 wherein the compound is 7-chloro-5-phenyl 1 methyl-3H-1,4-benzodiazepin-2( 1H)-one.

References Cited in the file of this patent FOREIGN PATENTS Australia Jan. 20, 1955 Australia Sept. 27, 1956 OTHER REFERENCES 

1. A NONAQUEOUS COMPOSITION SUITABLE FOR PARENTERAL INJECTION COMPRISING A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (A) A BENZODIAZEPINE HAVING THE FORMULA 